DNA methylation patterns are frequently aberrant in cancer cells. Thus, hypomethylation of intergenic regions can occur, leading to tumorigenesis via the activation of transposable elements and increased genomic instability. Local hypomethylation of genes promoters can promote oncogene expression, while local hypermethylation of the genes promoters can lead to loss of tumor suppressor function in cancer cells. Based on this last point, drug development has focused on DNA methylation inhibitors with the goal of activating tumor suppressor genes (TSG) silenced by DNA methylation. But in absence of specificity, a DNMT inhibitor can promote the demethylation of TSG but also of oncogenes and transposable elements. Thus, the use of unspecific DNMT inhibitors can be anti-tumorigenic or pro-tumorigenic. Besides, this last point is illustrated in several articles. Indeed, literature reports that 5-aza-2′-deoxycytidine treatment (an unspecific DNMT inhibitor) increased the invasiveness of non-invasive breast cancer cell lines MCF-7 cells and ZR-75-1 and dramatically induced pro-metastatic genes [Chik F et al., 2011]. 5-aza-2′-deoxycytidine treatment is also reported as an inducer of glioma from astrocytes and as an enhancer of tumorigenic property of glioma cells. Nevertheless, 5-aza-2′-deoxycytidine is approved by the Food and Drug Administration of the United States for the myelodysplastic syndrome treatment, where it demonstrates significant, although usually transient, improvement in patient survival. Despite this undoubtable clinical utility, the dual effect of the use of unspecific DNMT inhibitors provides evidence for the development of specific DNMT inhibitors. In addition, specific DNMT inhibitors could also allow targeting of tumors harboring an aberrant functionality of a particular DNMT. The development of specific DNMT inhibitors could also reduced off-target effects associated with the use of unspecific DNMT inhibitors.
At present, several molecules are developed to specifically target a particular DNMT. Thus, DNMT1 can be inhibited by using RG108, MG98 or Procainamide, DNMT3A while DNMT3B can be specifically inhibited by using Theaflavin 3, 3′-digallate or NanaomycinA, respectively [Amato R et al., 2012; Kuck D et al., 2010; Kuck D et al., 2010; Lee B et al., 2005 and Rajavelu A et al., 2001]. To identify these specific DNMT inhibitors, several strategies are developed: the docking-based virtual screening methods, the screening of natural products, the design and generation of derivatives of DNMT inhibitors already known, the molecular modeling of DNMT inhibitors by using crystal structure studies of DNMTs, or the design of siRNA targeting DNMTs [Kuck D et al., 2010; Medina-Franco J et al., 2011; Suzuki T et al., 2010; Yoo J et al., 2012; Yoo J et al., 2012 and Venza M et al., 2013]. In a recent article, we demonstrated that DNMT inhibitors can be also addressed against a specific DNMT/protein-x interaction [Cheray M et al., 2013].